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Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy

  • Autori: Alice Turdo; Antonino Glaviano; Giacomo Pepe; Federica Calapà; Stefania Raimondo; Micol Eleonora Fiori; Daniela Carbone; Manuela Giovanna Basilicata: Veronica Di Sarno; Carmine Ostacolo; Barbara Parrino; Stella Cascioferro; Camilla Pecoraro; Simone Di Franco; Diana Bellavia; Miriam Gaggianesi; Veronica Veschi; Melania Lo Iacono; Gloria Ganduscio; Vincenzo Davide Pantina; Laura Rosa Mangiapane; Maria Rita Bongiorno; Riccardo Alessandro; Matilde Todaro; Ruggero De Maria; Patrizia Diana; Pietro Campiglia; Giorgio Stassi
  • Anno di pubblicazione: 2021
  • Tipologia: Articolo in rivista
  • OA Link:


Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CRCSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell deathrelated genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.